Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation

Abstract Sequence-based machine learning models trained on genome-scale biochemical assays improve our ability to interpret genetic variants by providing functional predictions describing their impact on the cis-regulatory code. Here, we introduce a new model, Borzoi, which learns to predict cell- and tissue-specific RNA-seq coverage from DNA sequence. Using statistics derived from Borzoi’s predicted coverage, we isolate and accurately score variant effects across multiple layers of regulation, including transcription, splicing, and polyadenylation. Evaluated on QTLs, Borzoi is competitive with, and often outperforms, state-of-the-art models trained on individual regulatory functions. By applying attribution methods to the derived statistics, we extract cis-regulatory patterns driving RNA expression and post-transcriptional regulation in normal tissues. The wide availability of RNA-seq data across species, conditions, and assays profiling specific aspects of regulation emphasizes the potential of this approach to decipher the mapping from DNA sequence to regulatory function.